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Mood Disorder Research Led by SUNY Downstate’s Dr. Jeremy Coplan Suggests Early Life
Stress May Cause Excess Serotonin Release Resulting In A Serotonin Deficit Where the
Brain Needs It Most

Data Suggest a Reason Why SSRI Medications May Fail in Many Patients, and Why Depressed
Patients May Benefit from Strategic SSRI-Augmenting Treatment Approaches

Studies indicate that the majority of people with mood and anxiety disorders who receive
the most commonly prescribed class of antidepressant medications, Selective Serotonin
Reuptake Inhibitors or SSRI’s, are not helped by these medications. SSRIs are designed
to increase serotonin, a neurotransmitter in the brain that is key to maintenance
of mood.

Researchers led by Jeremy D. Coplan, MD, professor of psychiatry at SUNY Downstate
Medical Center, have published data suggesting an explanation for the longstanding
puzzle as to why low serotonin could not be detected in depression without suicidal
intent, even though many antidepressant treatments work by increasing serotonin in
areas key for mood regulation, such as the hippocampus. The pre-clinical research
was published in a recent edition of Frontiers in Behavioral Neuroscience.

Dr. Coplan explains, “We have shown that serotonin is too high near the serotonin
brain cells, reducing firing of the serotonin nerve cells through a well-documented
negative feedback mechanism in the raphe nucleus. The result is that the hippocampus
and other critical brain structures needed for mood maintenance do not get enough
serotonin. We can see this because the hippocampus is shrunken and the white matter
loses integrity. By the time serotonin metabolites are measured in a lumbar spinal
tap, the usual way serotonin levels have been measured, the high serotonin has mixed
with the low serotonin and you have no difference from people who are healthy.”

He continues, “We have hypothesized in an earlier paper that this is a plausible reason
why SSRIs may not work in a majority of people, because SSRIs will tend to make the
high serotonin even higher in the raphe nucleus. The serotonin neuron may not be able
to adapt and restore its firing, inducing a presumed serotonin deficit in terminal
fields, evidenced by shrinkage of the hippocampus.”

He adds, “We cannot say categorically, in our pre-clinical model, that high serotonin
in the raphe nucleus leads to low serotonin in the hippocampus, but studies by J.
John Mann, MD, a co-author on the paper, and Victoria Arango, PhD, both of Columbia
University Medical Center, have shown that people who committed suicide exhibited
high serotonin in the raphe nucleus and low serotonin in another area of the brain
critical for mood maintenance, the prefrontal cortex. Additional studies should be
performed, especially since better understanding of the serotonin system will significantly
improve future treatment options.”

In the earlier paper, also in Frontiers in Behavioral Neuroscience, Dr. Coplan proposed
augmentation therapies in treatment-resistant patients, including stacking one medication
upon another in the most difficult cases: “This is what physicians do for hypertension,
diabetes, and congestive heart failure,” said Dr. Coplan. “But in psychiatry, we sometimes
act as if our medications are so effective that we are exempt from how the rest of
medicine deals with difficult-to-treat cases.”

Other approaches to bypass the high midbrain serotonin impasse, according to Dr. Coplan,
are shutting glutamate input into the raphe nucleus, a portion of the brain that controls
the release of serotonin, and utilizing drugs that block noradrenergic input into
the dorsal raphe.

Dr. Coplan notes that a recent large-scale study showed only a minority of patients
do well on SSRIs, and of those, many lose response in a year or two. “There is an
epidemic of inadequately treated depression and psychiatrists are not well trained
to deal with this challenge,” he observed. “What they often do is change from one
antidepressant to another when there is a lack of response. Eventually the patient
becomes non-compliant and the patient, rather than the treatment, is blamed for the
non-efficacy.”

“These two papers provide possible insights as to why our treatments are ineffective
and what we should be doing to treat patients effectively,” Dr. Coplan said. “Many
academic researchers currently do not practice clinically, so they are out of touch
with real-life patients and their struggles. In the meantime, suicide rates have not
budged in decades.”

The content of these papers is solely the responsibility of the authors and does not
necessarily represent the official views of the NIH or other funders.

Dr. Arango’s and Dr. Mann’s work has also been funded by NIMH (R01-MH40210), with
Dr. Arango as principal investigator.

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About SUNY Downstate Medical Center

SUNY Downstate Medical Center, founded in 1860, was the first medical school in the
United States to bring teaching out of the lecture hall and to the patient’s bedside.
A center of innovation and excellence in research and clinical service delivery, SUNY
Downstate Medical Center comprises a College of Medicine, College of Nursing, School
of Health Professions, a School of Graduate Studies, School of Public Health, University
Hospital of Brooklyn, and a multifaceted biotechnology initiative including the Downstate
Biotechnology Incubator and BioBAT for early-stage and more mature companies, respectively.

SUNY Downstate ranks twelfth nationally in the number of alumni who are on the faculty
of American medical schools. More physicians practicing in New York City have graduated
from SUNY Downstate than from any other medical school.